Abstract
The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.
Highlights
The standard of care for patients with melanoma whose tumour burden is limited and disease spread is confined comprises surgical resection with the intention to cure
AE adverse event, CALM Coxsackievirus A21 in Late stage Melanoma, CR complete response, CVA cerebrovascular accident, DRR durable response rate, FAS full analysis set, GM-CSF granulocyte-macrophage colony-stimulating factor, HIT-IT human intratumoural immunotherapy, HR hazard ratio, IL-2 interleukin-2, irPFS immune-related progression-free survival, NR not reached, OPTiM Oncovex (GM-CSF) Pivotal Trial in Melanoma, OR odds ratio, ORR overall response rate, PR partial response, Talimogene laherparepvec (T-VEC) talimogene laherparepvec, TEAE treatment-emergent adverse event. aAgents included in this table are those for which monotherapy Phase 2 or 3 clinical trial data are available. bObjective response lasting continuously for ≥6 months. cReduction in lesion size by ≥50%. dUninjected non-visceral lesions
Data 894 indicate the existence of a synergy between HIT-IT and checkpoint inhibitors (CPIs), and it is likely that future clinical use will focus on the combined use of these agents; strategies that combine treatments that have different modes of action without overlapping toxicities are likely to feature in future research
Summary
The standard of care for patients with melanoma whose tumour burden is limited and disease spread is confined comprises surgical resection with the intention to cure. The need for additional treatment options for unresectable locoregional disease coupled with the accessibility of this type of metastasis has led to increased interest in immunostimulatory agents that can be injected directly into the tumour.[5] These intratumoural immunotherapies can cause cell lysis, either directly or indirectly, and promote the induction of a local immune response, and might be associated with the generation of a systemic immune response.[18,19]. AE adverse event, CALM Coxsackievirus A21 in Late stage Melanoma, CR complete response, CVA cerebrovascular accident, DRR durable response rate, FAS full analysis set, GM-CSF granulocyte-macrophage colony-stimulating factor, HIT-IT human intratumoural immunotherapy, HR hazard ratio, IL-2 interleukin-2, irPFS immune-related progression-free survival, NR not reached, OPTiM Oncovex (GM-CSF) Pivotal Trial in Melanoma, OR odds ratio, ORR overall response rate, PR partial response, T-VEC talimogene laherparepvec, TEAE treatment-emergent adverse event. AE adverse event, CALM Coxsackievirus A21 in Late stage Melanoma, CR complete response, CVA cerebrovascular accident, DRR durable response rate, FAS full analysis set, GM-CSF granulocyte-macrophage colony-stimulating factor, HIT-IT human intratumoural immunotherapy, HR hazard ratio, IL-2 interleukin-2, irPFS immune-related progression-free survival, NR not reached, OPTiM Oncovex (GM-CSF) Pivotal Trial in Melanoma, OR odds ratio, ORR overall response rate, PR partial response, T-VEC talimogene laherparepvec, TEAE treatment-emergent adverse event. aAgents included in this table are those for which monotherapy Phase 2 or 3 clinical trial data are available. bObjective response lasting continuously for ≥6 months. cReduction in lesion size by ≥50%. dUninjected non-visceral lesions
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